How a Vaccine is Made With Dr. Daniel Culver

Podcast Transcript

Deanna Pogorelc:  Hi. Welcome to the Health Essentials podcast brought to you by Cleveland Clinic. I'm your host, Deanna Pogorelc.

It's been about nine months since COVID-19 first came onto the world's radar, and there's a lot of talk about, and anticipation for, a potential COVID-19 vaccine. Today we're going to talk about vaccines: What's in them? What did they do? How do they work? And what's going on with development of a potential COVID-19 vaccine? Here to answer those questions is pulmonologist, Dr. Daniel Culver.

Welcome, Dr. Culver. Thanks so much for being here.

Dr. Culver:  Thank you for having me.

Deanna Pogorelc:  To our viewers and listeners, please remember that this is for informational purposes only and is not intended to replace your own health care provider's advice. It's also been prerecorded, and may not reflect any changes to the COVID-19 precautions or recommendations that have been made after the recording.

So Dr. Culver, can we set the stage for this conversation by talking a little bit about why vaccines are so important?

Dr. Culver:  Vaccines are a critically important part of our health, and there are many diseases now that were killers a century or two ago, which are now barely blips in our conscious. Polio is essentially eradicated, except for some very small pockets in remote areas of the world. Measles was a major childhood illness that caused a large number of deaths in the past and a lot of problems in society. There are many fewer flu deaths than there used to be. All of these things are attributable to widespread vaccination. So vaccination, I think, is one of the pillars of good public health.

Deanna Pogorelc:  When we talk about how a vaccine is made, what are the different components that go into a vaccine?

Dr. Culver:  Well, there are a number of different types of vaccines, and the type of vaccine really depends on the microorganism that's being targeted, and what's determined as the best way to get an immune system response to that microorganism.

Mostly we're vaccinating for either bacteria or viruses, and some of the vaccines that we use could use killed microorganisms. If you killed the virus so it can't infect anybody, that could then be injected.

There are also viruses that are called attenuated. Those may be living viruses, but they're no longer capable of causing significant illness. And those may be better for certain situations, and may induce nice immune responses.

Finally, there are other vaccines that just use parts of viruses, or some proteins from various microorganisms. And so again, that depends really on what will induce the best immune response, and also what can be used in widespread populations.

Deanna Pogorelc:  To get those components into a format that is able to be given to someone as an injection or some other form, are there any other ingredients that are put into a vaccine, specifically that might be a concern for someone who has allergies or is sensitive?

Dr. Culver:  Vaccines, by and large, are extremely safe. One question that comes up is allergy to vaccines, and allergy to vaccines is very rare. In general, allergy to vaccines is to the vaccine itself, not to the other components that are in the vaccine. There are some reports of allergies to vaccines, but most of those, in fact, are not allergies. Most reactions that people get from vaccines are normal reactions you would expect, like pain at the site of the injection, mild temperature, some achiness. This really means that the immune system is sitting up and taking notice of the vaccine. I always take that as a good sign; it means the immune system is paying attention.

One question that also comes up quite often is this issue of egg allergy. In fact, this has been looked at quite carefully, and it's no longer considered a contraindication for egg allergy to receive any vaccination, except perhaps with the possibility of the yellow fever vaccination.

The issue about not giving a flu vaccine in people with egg allergy has been studied very carefully; the levels are extremely low. The rates of true allergic reactions in people with egg allergy are exceedingly low, and so all the major organizations recommend not considering egg allergy as a contraindication to vaccination.

The other one that comes up with vaccinations is whether or not people on antibiotics, or who have had recent viral illnesses, or who are getting other vaccines around the same time should be vaccinated. In fact, all of those are myths. You can be vaccinated in all those situations, and if you have the opportunity to get vaccinated, we would recommend just going ahead and taking the opportunity while it's there.

Deanna Pogorelc:  Absolutely. How can some vaccines, like MMR for example, protect us from more than one thing?

Dr. Culver:  Some vaccines are combination vaccines. MMR is measles, mumps, and rubella, and that's a triple threat vaccine. DPT is another example of that, with diptheria, pertussis, and tetanus. And so, vaccines like influenza may only cover one microorganism, but these are combinations. And the reason, I think, that they're combined is that during childhood immunizations, there's a schedule for them, and these all fit onto the same schedule.

Deanna Pogorelc:  Who's developing vaccines? I know when it comes to COVID-19, we've heard there are several under development. Is it happening in research labs, or are they drug companies, or how does that work?

Dr. Culver:  Right. COVID-19 vaccines are really being developed at a very rapid pace in a broad partnership between the biopharmaceutical industry partnering with academic institutions in many situations, and with a lot of support by agencies in the federal government. And this is governments around the world. There are also transnational organizations that are involved, like Vaccine Alliance and other organizations. These are all working in partnership to try to move this very, very fast.

Deanna Pogorelc:  Yeah. Speaking of very fast, how long does it typically take for a vaccine to go from research to being available to the public?

Dr. Culver:  The usual timelines for developing a vaccine is certainly more than 10 years, and probably closer to 15 or even 20 years. And that's because these are usually being done in the context of a single company that goes through sequential steps, and that wants to reevaluate at each step whether or not there's efficacy, whether or not there's safety, and whether or not they're hitting the target correctly. And so, these steps typically involve preclinical testing, followed by different phases of clinical trials, and finally a process of regulatory approval, and then the process of manufacturing and distribution.

In the current situation, because of the pandemic and the crisis that we're experiencing, these steps have been telescoped. I don't think that we are missing important parts of these steps; I think what we've done is we've collapsed many of these steps together so that they're overlapping. And much of the risk, in fact, now is being taken by the federal government, so that manufacturing is happening even before we know whether certain vaccines are going to be effective. And then, if they do be shown to be effective, we can go ahead and start distributing those almost immediately.

Deanna Pogorelc:  Can you talk a little bit more about those clinical trials and what it means when we hear phrases like phase three, phase two, phase one? What are the purpose of all of those?

Dr. Culver:  Clinical trials go through proscribed steps. Phase one is generally a trial with a very small number of people to demonstrate safety, and also to look and see whether or not the body can generate immune responses to the vaccine. And so blood will be drawn, antibody levels will be measured, levels of cell responses of the immune cells will be measured. In fact, the companies are trying to make sure that the vaccine is able to do what they think it should be doing, in terms of the immune response.

After phase one, generally then the data are analyzed and a phase two trial gets started, which is a larger trial; maybe that's on the order of several hundred to a couple of 1000 patients, typically. And that's looking more at the dose. That's looking at a broader swath of patients ... maybe patients who have some chronic medical conditions, older patients, younger patients ... again, to demonstrate efficacy and safety.

Finally, the last stage is the stage three, and that's really looking at a very large trial, trying to demonstrate that the vaccine can actually stop the disease. And so in general, some people will get the vaccine. Other ones will get a placebo, which is a substance that looks exactly like the vaccine, but it doesn't actually have the vaccine in it. And then those people will be followed over time, to see if there's a difference in the rates of infection between placebo and active treatment.

After phase three is over and all the data have been analyzed, both for efficacy and for safety, then those data are presented to regulatory agencies, like the FDA, for an assessment about whether this should be widely available.

Deanna Pogorelc:  Do those clinical trials involve people of all ages, of all levels of health or sickness?

Dr. Culver:  Earlier phase clinical trials tend to focus more on healthier populations. As the trials go along, they're generally expanded to patients at the extremes of age, other populations, like patients with mild to moderate immunosuppression, patients who have multiple chronic medical conditions, pregnant women ... populations where you wouldn't want the first people out of the gate to be exposed to a vaccine that you don't know that much about, yet you want to know for sure that the vaccine is okay for those populations.

Deanna Pogorelc:  Can you talk a little bit more about the regulatory process here in the US, and what kind of data do companies need to show to have their product approved?

Dr. Culver:  The regulatory process here in the US, like much of the rest of the world, really takes into account the entirety of the data in order to determine whether, on balance, vaccine is going to be helpful for populations. And so, regulators look at evidence from early stage clinical trials, even data from lab experiments before the medicine gets into humans. Then they look at all of the data from the clinical trials, both looking at the effectiveness, as well as the safety of the vaccine.

And finally, they look at a rare side of it, side effects or events that happen, that can only be seen in the very large clinical trials. You could imagine that if something very uncommon happens ... it might only happen in one in 5,000 subjects ... that you might not see that until the phase three trial. And so, the regulators are going to look at all of those factors, and then they're going to make the determination on whether or not this is a product that actually will be helpful for the US population.

Even after approval, there will be ongoing monitoring for side effects. In fact, sometimes vaccines and other medications are pulled back out of the market because previously unrecognized problems are identified.

Deanna Pogorelc:  Now I want to ask how vaccines work. Once they go into our bodies, what happens? How do they stimulate that immune response?

Dr. Culver:  Once a vaccine is administered, ideally the immune system will notice it, it will perceive it as foreign, and it will generate an immune response. The immune response will be using two different arms of the immune system. One arm of the immune system is antibodies, which are proteins that our immune cells produce that bind to the microorganism and help neutralize it and help destroy it. And the other arm of the immune system is the cellular arm of the system, where immune cells will circulate and help to fight off the virus by destroying and neutralizing our immune-infected cells.

So both of those arms of the immune response, ideally, will be generated by a good vaccine, and both will be very important for immunity following vaccine.

Deanna Pogorelc:  Why are there different delivery systems for vaccines? Like for example, the flu nasal spray ... I've heard there's talk about an oral vaccine for COVID-19. Why is that possible?

Dr. Culver:  Depending on where the immunization happens, there may be slightly different versions of immunity. The way our immune system responds, for example, in the cells in the lining of the nose, or the cells in the lining of the intestine is different than, for example, in the blood or in the lymph nodes of the body. And certain situations might be better served by having good immunity in the nose and the mouth, or good immunity in the intestine.

That doesn't mean that if we get a pill form of a vaccine, that you won't generate a response throughout your body. In fact, that's how the oral polio vaccine works, for example. But there are some nuances, and there are some situations where it might be beneficial to get augmented immunity in those particular situations.

One could imagine, for example, with influenza, which tends to spread through respiratory droplets, that having good immunity in the nose would help block influenza a little bit more effectively than a shot.

Deanna Pogorelc:  Why are some vaccines good for life while others require either a booster shot, or like the flu shot, we have to get it annually?

Dr. Culver:  There are two components to how often vaccine needs to be delivered. One of them is that for certain microorganisms, either because of the nature of the immune response or the microorganism itself, the immune response wanes over time. So you see that, for example, with MMR, where booster shots are needed periodically in order to maintain good immunity. And you can think about that as if your immune system is forgetting about what it has seen before.

There are also other situations where the main targets of the immune system shift over time. We see that with influenza, where the proteins that our immune system is interested in shift slightly from year to year. And that's why we get a seasonal influenza vaccine, because we're trying to predict which proteins are going to be on this particular season's influenza virus, and will therefore induce a nice response from our immune system with a vaccine.

Those are both of the reasons why we have to update vaccines for some things, but not for others.

Deanna Pogorelc:  What can we expect from a vaccine? Do they prevent us entirely from becoming infected with the virus or bacteria, or do they prevent an infection from getting bad, or do they prevent us from being able to spread it to other people, or all of those?

Dr. Culver:  There are vaccines that really blunt the response to an infection, and I think that's the main goal. I think with these COVID vaccines, that will be the main goal. We probably will not see what's called sterilizing immunity. That is that there is no virus whatsoever in people exposed to it. But you can imagine that if their level of virus is very low, because you have effective immunity; number one, you might not get very sick. Number two, you might not spread it around very easily, or whatever virus you're shedding might already be dead. And finally, you can imagine that then we would have much less impact on the healthcare system.

So I don't think sterilizing immunity is necessarily what we need to achieve. We need to achieve a vaccine that really turns down the temperature dial on the infection.

Deanna Pogorelc:  Yeah. We hear that getting a vaccine doesn't just protect you, but it also protects those around you. What does that mean?

Dr. Culver:  All of these viruses depend on transmission from person to person. As more and more people are immune to a virus, or at least don't shed any significant amount of the virus, there are more and more people we might contact during our daily lives who can't give us the virus. And if that number gets high enough, then we'll have what's called herd immunity, where even if there are a few people in the population who are completely susceptible to the virus, there just aren't enough people around to really spread it in any kind of significant way.

And so, what we would like to see is that for every infected person, the number of people who are subsequently infected is as low as possible. And if we can keep that number below one, then we would see that the number of virus cases would go down over time.

Deanna Pogorelc:  I want to ask you about some common vaccine myths. You've hit on this a little bit, a couple of these, but maybe we can just reiterate, the first one being side effects. Do vaccines cause you to get sick with the virus or bacteria they're supposed to prevent you from getting?

Dr. Culver:  Vaccines do not cause you to get the illness that you are being vaccinated against. However, vaccines can cause immune reactions; in very rare circumstances these can be serious.

The much more common thing is to develop a bit of a reaction where your immune system is taking notice of the vaccination. Fever, pain at the injection site, a headache... those are very common side effects. I always think it's good to see those things, because it means that your immune system is paying attention. And if you don't see those, then you wonder whether or not your immune system really noticed it.

Deanna Pogorelc:  The second one is: have certain vaccines been linked to autism? And where did this idea come from?

Dr. Culver:  The link between vaccinations, especially MMR, and autism has been postulated for several decades. I think it's important for everybody to know that the original paper that described this has been discredited. It was thrown out, and in fact, the data were found to be false and manipulated.

Since that time, a number of people have taken up the idea that vaccines are associated with autism. And part of the reason for that is the time when symptoms of autism first appear in childhood is pretty similar to the time when vaccinations are being given during childhood. And so, some people have believed that these two things were linked.

I want to point out that there are a lot of epidemiologic studies, involving tens of thousands of children, that found no link between autism and receiving vaccines. And in fact, there are a couple of studies that show that as the rate of MMR vaccination decreased, the rate of autism actually increased. There are at least two studies that show that vaccination might actually be associated with less risk of autism, not more risk of autism.

I think we need to put this idea to bed, once and for all.

Deanna Pogorelc:  And then the third myth: Can multiple vaccinations overwhelm the immune system, or is it dangerous to get multiple near the same time?

Dr. Culver:  You should speak to your doctor about your vaccination schedule. However, in general, it's perfectly safe to receive several vaccinations at the same time, because the cells that recognize each particular vaccine are different cells, and they're all doing their own jobs in isolation.

Deanna Pogorelc:  Now I'd like to move into talking a little more specifically about this potential COVID-19 vaccine or vaccines. Where do we stand currently with development and progress toward a COVID-19 vaccine?

Dr. Culver:  The COVID-19 vaccine programs are going very, very quickly. I think the moniker Operation Warp Speed is absolutely spot on.

These vaccines are being developed very safely, and all the steps that are necessary are being taken, as far as I can tell. However, we're collapsing several of these steps together, so that we'll get an answer much faster than we typically would.

Right now, there are a number of phase three trials going on, five or six in the US right now, that are enrolling tens of thousands of patients. Several of them have just about completed enrollment, and we expect to see that results of these things may be available sometime around the end of the year, or the first quarter of 2021.

Vaccines in general are difficult to develop; may look very good in early phase trials, but may not be effective in phase three trials. So I think it's very important to know that there are nearly 200 vaccines currently in development, in various stages of clinical testing, and that we need a lot of possible chances to find an effective vaccine, because there'll be different populations that react differently to certain vaccines. And some of the ones that are currently the most popular may turn out to be not as effective as some of the ones that are a little further behind.

Deanna Pogorelc:  You talked earlier about some of the different types of vaccines, and how they can be made differently. Are different developers of COVID-19 vaccines taking different approaches or the same approach?

Dr. Culver:  There are a number of platforms, some of which are quite novel and use really cutting edge technology for development of these vaccines. A lot of these use genomic technology, using RNA or DNA.

When the sequence of the SARS-CoV-2 was published, a number of groups immediately took that, started developing constructs and making RNA-based vaccines, and DNA-based vaccines, and even protein subunit-based vaccines as different strategies to try to develop effective vaccines. And so, this has allowed us to be very quick compared to the conventional inactivated or live attenuated vaccines.

There are all of these different platforms being used in multiple instances for different developers. For example, the Moderna vaccine or the Pfizer vaccine that you've heard about are RNA vaccines. Johnson and Johnson has a vaccine that's based on a viral vector; that is taking a relatively benign common cold virus called an adenovirus, making it unable to reproduce so that it can't even cause a cold, and then putting the code for the viral spike protein from the COVID into it so that when we get that adenovirus vector, we start making that protein, and our immune system notices it, and we get immunity to SARS-CoV-2. So this is called a viral vector vaccine. That's also what's being used by AstraZeneca, for example.

So again, multiple people are trying different strategies. We're going to see which of these is the most effective. And certainly, I hope that more than one of these is effective.

Deanna Pogorelc:  In these clinical trials, how do we know that a vaccine is effective? What's the technique for showing that it's effective?

Dr. Culver:  Different companies are taking slightly different techniques. In the phase three trials, they're really looking for the development of infection. And that can either mean symptomatic infection; that is you develop an illness and you have testing that shows that you have COVID. Or some companies are even taking the strategy of saying, "We want to block significant infection;" that is infection causes you to need to go to the hospital, or to be particularly debilitated. So really blocking significant infection, or blocking symptomatic infection is what we need to do.

All the companies are also looking at the chance of just developing asymptomatic infection. They're looking at how your immune system responds to the vaccine. They're looking at a whole host of other markers, but I think the main thing is: do we stop people from becoming infected in a way that causes symptoms?

Deanna Pogorelc:  Are there signs that the coronavirus that causes COVID-19 is mutating? And if so, would that affect the development of a vaccine?

Dr. Culver:  There are several strains of the SARS-CoV-2. There tends to be one dominant strain right now in most of the world.

I think it's important to know that the SARS-CoV-2, the virus that causes COVID, is very dependent on the spike protein for entry into human cells. And there are parts of that spike protein that are unable to mutate very much because they're very necessary for the virus to do its work.

And so, I think that there will be mutations, but these tend to be relatively small. They tend not to cause big shifts in the antigenic, or the immune system properties of the virus. And so there may be need to tweak the vaccines over time, but I don't think you're going to see rapid shifts in vaccines, like we see with the flu every year, for example, with this particular vaccine. What we're more likely to see with this vaccine is that the immune system immunity wanes over time, and so boosters may be necessary periodically. And the frequency of that remains to be determined.

Deanna Pogorelc:  Who will decide when a COVID-19 vaccine is ready to be used by the public?

Dr. Culver:  The decision about granting approval, or at least what's called an emergency use authorization, which would allow us to start using it in the setting of an emergency, will really be made by the FDA after they look at all the data. The FDA has just released a new guidance on that, and one of the things that's in there is that they have to see at least two months of safety data in vaccinated population before they would allow emergency use authorization, or any other form of authorization. And so, in fact, I think we can be reassured that there will be a scientifically rigorous and credible process before the decision to release any of these vaccines to the American public in a widespread way happens.

Deanna Pogorelc:  Great. I'm going to ask you a million dollar question. Will a vaccine end the pandemic?

Dr. Culver:  I don't think a vaccine will end the pandemic. I think a vaccine will be part of the solution to getting control over this, but I think it's highly unlikely that a vaccine will be a 100% effective, and will be used by enough of the population, regularly enough, to completely eliminate this virus from our world.

And so I think we'll need to have a strategy of several different things, including vaccination, including continued social distancing measures, including rigorous and adequate testing, and including contact tracing. And I think if we can combine all of those elements together, we can get back to something that's very close to a normal life in a couple of years from now.

Deanna Pogorelc:  In the meantime, what are some of the things that we should be doing to keep ourselves healthy?

Dr. Culver:  Everybody's getting tired of doing the things we should be doing, and yet they remain critically important. So in the meantime, until we have an effective vaccine, and even after we have an effective vaccine, I think good social distancing, listening to healthcare experts who are monitoring things, and thinking about how much we need to do social distancing, and what the right parameters are at the current time, based on local issues, and on national international issues. Of course, wearing masks in the appropriate setting, maintaining distance, staying out of crowds ... all those things that we've heard about for several months now remain absolutely just as important.

I think it's really important to remember that the extent to which we can open the economy, the extent to which we can go back to school, the extent to which we can do the sorts of things that we all enjoy as part of life really depends on personal responsibility from each of us.

And so, even though it's a marathon, we need to stick with the marathon because you're doing it not just for yourself, you're doing it for everybody else in the country. And if we're not able to do that, we're going to see again, fluctuations and spikes, like we saw in June and July after we let our foot off the gas pedal.

Deanna Pogorelc:  Right. Well, is there anything that we haven't discussed that you think is important to leave our audience with, or any kind of final takeaways you want to share?

Dr. Culver:  I think it's important for people to recognize that even though there has been a lot of different messaging about the virus ... and part of that is because there are many different people talking, and part of that is because the information is changing so fast ... even though there's been tremendous confusion about the virus at times, the process of developing this vaccine is being done very rigorously. And so, once a vaccine is approved by the FDA, and we can look at the data, and look at the rates of adverse events and significant side effects, that this is likely to be a very safe vaccine. So I don't want people to conflate the confusion, and all of the noise around COVID and the vaccines themselves, with the idea that there's a lack of rigor and lack of transparency that would let us take the vaccine effectively, and be safe and feel good about it.

Deanna Pogorelc:  Great. Well, thank you so much for that, and for answering all of those questions. We really appreciate you being here.

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